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-Structure paper
タイトル | Mechanism of NMDA Receptor Inhibition and Activation. |
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ジャーナル・号・ページ | Cell, Vol. 165, Issue 3, Page 704-714, Year 2016 |
掲載日 | 2016年4月21日 |
著者 | Shujia Zhu / Richard A Stein / Craig Yoshioka / Chia-Hsueh Lee / April Goehring / Hassane S Mchaourab / Eric Gouaux / |
PubMed 要旨 | N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated, calcium-permeable ion channels that mediate synaptic transmission and underpin learning and memory. NMDAR dysfunction is directly ...N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated, calcium-permeable ion channels that mediate synaptic transmission and underpin learning and memory. NMDAR dysfunction is directly implicated in diseases ranging from seizure to ischemia. Despite its fundamental importance, little is known about how the NMDAR transitions between inactive and active states and how small molecules inhibit or activate ion channel gating. Here, we report electron cryo-microscopy structures of the GluN1-GluN2B NMDA receptor in an ensemble of competitive antagonist-bound states, an agonist-bound form, and a state bound with agonists and the allosteric inhibitor Ro25-6981. Together with double electron-electron resonance experiments, we show how competitive antagonists rupture the ligand binding domain (LBD) gating "ring," how agonists retain the ring in a dimer-of-dimers configuration, and how allosteric inhibitors, acting within the amino terminal domain, further stabilize the LBD layer. These studies illuminate how the LBD gating ring is fundamental to signal transduction and gating in NMDARs. |
リンク | Cell / PubMed:27062927 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 7.0 - 15.4 Å |
構造データ | EMDB-8097, PDB-5iou: EMDB-8098, PDB-5iov: EMDB-8101, PDB-5ipq: EMDB-8102, PDB-5ipr: EMDB-8103, PDB-5ips: EMDB-8104, PDB-5ipt: |
化合物 | ChemComp-GLY: ChemComp-GLU: ChemComp-QEM: |
由来 |
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キーワード | SIGNALING PROTEIN / ligand-gated ion channel / synaptic transmission |